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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賴逸儒(I-Rue Lai) | |
| dc.contributor.author | Shin-Yun Liu | en |
| dc.contributor.author | 劉心雲 | zh_TW |
| dc.date.accessioned | 2021-06-15T13:26:30Z | - |
| dc.date.available | 2017-08-26 | |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-03-23 | |
| dc.identifier.citation | 1. Lindsey A., Bray F,Rebecca L., Ferlay J ,Joannie L, Jemal A Global cancer statistics, 2012.CA Cancer J Clin 2015;65:87–108.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51164 | - |
| dc.description.abstract | 異常的醣化作用影響癌細胞的惡性度。乙烯半乳糖胺轉移酶(N-acetylgalactosaminyltransferase 2, GALNT2)屬於黏液型醣基酵素，作用於醣化反應的起始步驟。本研究發現GALNT2 透過修飾肝細胞生長因子接受器(HGFR，又稱MET)，能夠抑制胃腺癌(GCA)的惡性程度。胃腺癌組織中mRNA 與protein 的GALNT2表現比正常的胃腺組織少， 發現GALNT2的表現量與胃癌病患的惡性度有關， GALNT2表現較少的病患其存活率較低。抑制胃癌細胞株GALNT2的表現，會增加胃癌細胞的惡性度；包括提升癌細胞的生長、轉移和侵襲行為。相反的，提高胃癌細胞GALNT2的表現時，胃癌細胞的惡性度降低。動物實驗發現，輸注GLANT2表現受抑制的胃癌細胞株,會增加胃癌細胞在裸鼠體內的轉移。在訊息傳遞的研究中發現，抑制胃癌細胞GALNT2的表現會改變MET 上的醣基構造，也會促進MET 的磷酸化。增加細胞內GALNT2的表現時MET 的磷酸化則減少。添加MET抑制劑，PHA665752，會抑制GALNT2 引起的GCA 惡性行為，顯示GALNT2影響GCA的惡性程度是經由修飾MET引起的。本研究發現GALNT2 的表現與胃腺癌惡性行為有關。提高GALNT2的表現可抑制胃腺癌細胞惡性度，提供MET上O-醣基化的改變對MET活性的影響和胃腺癌發展的重要見解。
關鍵字: 乙烯半乳糖胺轉移酶, O-醣基化, 肝細胞生長因子接受器, 胃腺癌 | zh_TW |
| dc.description.abstract | Aberrant glycosylation determines the malignant characters of cancers. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), an enzyme that mediates the initial step of mucin type-O glycosylation, suppresses malignant phenotypes in gastric adenocarcinoma (GCA) by modifying the activity of the MET (Hepatocyte growth factor receptor). GALNT2 mRNA and protein were downregulated in GCAs, and these events were associated with more advanced disease and shorter recurrence-free survival. Suppressing GALNT2 expression in GCA cells increased cell growth, migration, and invasion in vitro, and tumor metastasis in vivo. Mechanistic investigations revealed that GALNT2 knockdown enhanced phosphorylation of MET and overexpression of GALNT2 decreased MET phospohrylation. We also revealed that GALNT2 effected the Tn antigen on MET. Inhibiting MET activity with PHA665752 decreased the malignant phenotypes caused by GALNT2 knockdown in GCA cells, establishing the important role of MET in the effects mediated by GALNT2. Our results indicate that GALNT2 suppresses the malignant potential of GCA cells and provide novel insights into the significance of O-glycosylation in MET activity and GCA progression.
Keywords: GALNT2, N-acetylgalactosaminyltransferase, O-glycosylation, Hepatocyte growth factor, Receptor tyrosine kinase, gastric adenocarcinoma (GCA) | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T13:26:30Z (GMT). No. of bitstreams: 1 ntu-105-D99446007-1.pdf: 8720530 bytes, checksum: b2a4e03523c060e145efaee4f689ee10 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | Signature of Committees………………………………………………….. ii
Acknowledgement………………………………………………………..iii Summary of Dissertation in Chinese……………………………………….5 Summary of Dissertation in English……………………..………..……….6 Chapter 1. General Introduction………………………….………………7 1.1. Gastric cancer………………..…...…………………...….…………..7 1.2. Glycosylation and GALNT2………...…………….…………………7 1.3. Phospho-RTK and GALNTs ……...…………………………....…8 Chapter 2. Specific aims…………………………………...……………10 Chapter 3. Materials and methods…………………..…………………..11 3.1. Cell culture………………………………………..………………….11 3.2. Tissue immunohistochemistry …………………..…………………...12 3.3. Western Blot analysis……………………………..………………….13 3.4. Real-time reverse transcription (RT-PCR)…..……………………….13 3.5. Cell viability…..………………………..….…………………………14 3.6. Transwell migration assay ……………….…………………………..14 3.7. Matrigel invasion assay………..……………...……………………...15 3.8. siRNA knockdown of GALNT2 expression in gastric cancer cells.....15 3.9. Overexpression of GALNT2 in gastric cancer cells…………………15 3.10. Plasmids and construction of stable transfectants……..……………16 3.11. Tumor metastasis in nude mice……………………………………..17 3.12. Phospho-receptor tyrosine kinase array…………………………….17 3.13. Lectin pull down assay……………………………..………….…...18 3.14. Gene expression profiling and quantitative RT-PCR validation..…..18 3.15. Statistical analyses……………………………………………….....19 Chapter 4. Results…………………………………………………..…..21 4.1. Expression of GALNT2 is frequently down-regulated in huan Gastric carcinoma………………...…………………………………………………21 4.2. Knockdown of GALNT2 in gastric cancer cell lines ………….……22 4.3. GALNT2 suppresses malignant phenotypes in vitro…………...……22 4.4. GALNT2-knockdown increases tumor metastasis in nude mice….…23 4.5. GALNT2 knockdown increased HGF-induced activation of MET phospholation and the malignant potentials in gastric cancer cells………………………………………………………………....24 4.6. GALNT2 modulates O-glycosylation of MET………………….......25 4.7. GALNT2 knockdown increased the expression of MET in gastric cancer…………………………………………………………….…25 4.8. GALNT2 suppression affects gastric cells gene expression pattern……………………………………………………….……….26 Chapter 5. Discussion……………………………………….….………27 Chapter 6. Future work………………………………………...………..31 Chapter 7. References…………..…….……………...………………….32 Chapter 8. Figures and legend………………………….……………….37 Figure 1……...……………………….……………………….…………37 Figure 2………………………………………………………………….38 Figure 3………………………………………………………………….39 Figure 4………………………………………………………………….40 Figure 5………………………………………………………………….41 Figure 6………………………………………………………………….42 Figure 7………………………………………………………………….43 Figure 8………………………………………………………………….44 Figure 9…………………………………………………….……………46 Figure 10……………………………………………………………..….47 Figure 11………………………………………..……………………….48 Figure 12…………..…………………………………………………….49 Table 1………………………………………………..………………….50 Table 2……..…………………………………………………………….51 Appendix (published papers) …………………………...………………52 | |
| dc.language.iso | en | |
| dc.subject | 胃腺癌 | zh_TW |
| dc.subject | 胃腺癌 | zh_TW |
| dc.subject | O-醣基化 | zh_TW |
| dc.subject | 乙烯半乳糖胺轉移? | zh_TW |
| dc.subject | 乙烯半乳糖胺轉移? | zh_TW |
| dc.subject | O-醣基化 | zh_TW |
| dc.subject | 肝細胞生長因子接受器 | zh_TW |
| dc.subject | 肝細胞生長因子接受器 | zh_TW |
| dc.subject | O-glycosylation | en |
| dc.subject | GALNT2 | en |
| dc.subject | N-acetylgalactosaminyltransferase | en |
| dc.subject | O-glycosylation | en |
| dc.subject | Hepatocyte growth factor | en |
| dc.subject | Receptor tyrosine kinase | en |
| dc.subject | gastric adenocarcinoma (GCA) | en |
| dc.subject | GALNT2 | en |
| dc.subject | N-acetylgalactosaminyltransferase | en |
| dc.subject | Hepatocyte growth factor | en |
| dc.subject | Receptor tyrosine kinase | en |
| dc.subject | gastric adenocarcinoma (GCA) | en |
| dc.title | 黏液蛋白醣化酵素GALNT2經由修飾MET受體
調控胃癌的惡性程度 | zh_TW |
| dc.title | Mucin Glycosylating Enzyme GALNT2 Regulates the Malignant Character of Gastric Adenocarcinoma by Modifying the MET Receptor | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 黃敏銓(Min-Chuan Huang) | |
| dc.contributor.oralexamcommittee | 葉添順(Tien-Shun Yeh),孫家棟(Chia-Tung Shun),李宜家 | |
| dc.subject.keyword | 乙烯半乳糖胺轉移?,O-醣基化,肝細胞生長因子接受器,胃腺癌, | zh_TW |
| dc.subject.keyword | GALNT2,N-acetylgalactosaminyltransferase,O-glycosylation,Hepatocyte growth factor, Receptor tyrosine kinase,gastric adenocarcinoma (GCA), | en |
| dc.relation.page | 73 | |
| dc.identifier.doi | 10.6342/NTU201600130 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-03-23 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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